{"id":67934,"date":"2012-09-01T00:00:00","date_gmt":"2012-09-01T03:00:00","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/?p=67934"},"modified":"2012-12-19T21:46:56","modified_gmt":"2012-12-19T23:46:56","slug":"the-increased-production-of-vaccines","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/the-increased-production-of-vaccines\/","title":{"rendered":"The increased production of vaccines"},"content":{"rendered":"

Published in july\u00a02011<\/em><\/p>\n

With the capacity to produce\u00a020 million doses,\u00a0the flu vaccine plant\u00a0at the Butantan Institute\u00a0became fully\u00a0functional in March and should ensure\u00a0Brazil\u2019s self-su\u0002ciency in the prevention\u00a0of influenza in the elderly in 2012. This\u00a0plant was inaugurated in 2007, but the\u00a0plant\u2019s processes were validated only recently.\u00a0In three to five years, the country\u00a0could potentially become an exporter of\u00a0influenza vaccines. Two technologies\u00a0developed by researchers at Butantan\u00a0promise to increase production without\u00a0the need to expand the plant or purchase\u00a0more raw materials. Each dose requires\u00a0the use of a fertilized chicken egg for the\u00a0reproduction of the virus, and the plant\u00a0uses 20 million eggs per year to produce\u00a0viruses. One of the new technologies\u00a0permits the whole virus to be isolated,\u00a0including all of the proteins. Current\u00a0vaccines against the influenza virus are\u00a0based on one protein, hemagglutinin A.\u00a0The remaining proteins are discarded,\u00a0but they can also provide protection.\u00a0In addition, these other proteins accumulate\u00a0fewer mutations over time than\u00a0hemagglutinin A. \u201cWhen we produced\u00a0this new vaccine, we found that production\u00a0per egg increased from two to seven\u00a0times, depending on the serotype of the\u00a0virus,\u201d says Isaias Raw, a researcher at\u00a0the Butantan Institute.<\/p>\n

The second technology, already patented\u00a0by the institute, allows for the\u00a0isolation an adjuvant substance, monophosphoryl\u00a0lipid A (MPLA), which
\nenhances the body\u2019s immune response\u00a0by stimulating the production of appropriate\u00a0antibodies or lymphocytes. Other\u00a0adjuvant substances have already been\u00a0created, but they are expensive or inaccessible.\u00a0MPLA, curiously enough, is the\u00a0byproduct of another line of research by\u00a0Butantan that involves the development\u00a0of a new type of pertussis vaccine that is\u00a0considered safer due to the removal of\u00a0lipopolysaccharide (LPS), which causes\u00a0inflammatory and toxic reactions, from\u00a0the bacteria. \u201cWe convert pounds of LPS\u00a0into MPLA, which in small quantities\u00a0can increase the responses to several\u00a0vaccines so that they can be used in\u00a0lower doses,\u201d says Isaias Raw. Tests on\u00a0mice showed that MPLA can allow the\u00a0vaccine to protect against influenza using\u00a0just a quarter of the currently used\u00a0dose. This e\u0094ect has already been demonstrated\u00a0in human beings.<\/p>\n

This substance is being tested against\u00a0various diseases. Butantan demonstrated\u00a0that MPLA has the potential for use in\u00a0canine leishmaniasis vaccines. These\u00a0vaccines can break the transmission cycle\u00a0of the disease, which can be deadly\u00a0to humans. MPLA is also the subject of\u00a0investigations by researchers at the Ludwig\u00a0Institute in New York, who seek to\u00a0enhance the e\u0094ect of a vaccine against\u00a0ovarian cancer, and researchers from\u00a0Ribeirao Preto, who are working on a\u00a0vaccine against tuberculosis. \u201cSoon, it\u00a0will also be evaluated with a hepatitis\u00a0B vaccine that is now ine\u0094ective in\u00a0people over 50 who are awaiting kidney\u00a0or liver transplant,\u201d says Isaias Raw. By\u00a0increasing the immune response, MPLA\u00a0also makes the vaccine less specific,\u00a0and cases in which a flu vaccine immunized\u00a0against serotypes not included in\u00a0the vaccine have already been detected.\u00a0MPLA is also inexpensive. \u201cWe can produce\u00a0enough MPLA to manufacture 1\u00a0billion doses at a cost of just pennies.\u00a0This makes Brazil immune to pressure\u00a0from large pharmaceutical companies\u00a0that do not want to sell the adjuvant but\u00a0only the complete vaccine itself,\u201d says\u00a0the researcher. The results, which must\u00a0be validated in new clinical trials before\u00a0the vaccine reaches the production line,\u00a0were published in the journal Vaccine in\u00a0an article by Raw, Cosue Miyaki, Wagner\u00a0Quintilio and Eliane Miyaji, among\u00a0other researchers at the institute. \u201cThe\u00a0research does not end with the publication\u00a0of the article but with the production of vaccines to meet public demand,\u201d\u00a0says Isaias Raw.<\/p>\n

Butantan believes that both technologies\u00a0have the potential to increase the\u00a0plant\u2019s production capacity for the influenza\u00a0vaccine from 20 million to 160
\nmillion doses. Such growth, after the\u00a0completion of clinical trials, will naturally\u00a0depend on market conditions, which\u00a0have varied greatly in recent years. The\u00a0plant was designed in 2004, when avian\u00a0flu was a threat. Caused by the H5N1\u00a0virus, the flu outbreak in 2005 resulted\u00a0in the death of thousands of birds and\u00a0hundreds of humans in Vietnam, Thailand,\u00a0Indonesia, China, Egypt and Cambodia.\u00a0At that time, an old building at\u00a0the Butantan Institute was converted\u00a0into a pilot laboratory to start experimenting\u00a0with small-scale production of\u00a0the influenza vaccine. Simultaneously,\u00a0funding was obtained from the state of\u00a0S\u00e3o Paulo to build a plant and from the\u00a0Ministry of Health to import the necessary\u00a0equipment. The technology for\u00a0vaccine production was transferred to\u00a0the Charles Merieux laboratory, now\u00a0called Sanofi-Pasteur, and is based on\u00a0the reproduction of the virus in fertilized\u00a0chicken eggs.<\/p>\n

The picture changed radically in 2009\u00a0with the emergence of the H1N1 virus,\u00a0which causes swine flu. This virus appeared\u00a0in the United States, infected\u00a0thousands of Mexicans, and quickly\u00a0caused a pandemic. The pandemic strains\u00a0were similar to those that caused the 1918\u00a0influenza pandemic, the so-called Spanish\u00a0flu that killed 40 million people. Both\u00a0viruses primarily a\u0094ect young children\u00a0and pregnant women, a sector of the population\u00a0that was not previously targeted\u00a0by vaccination campaigns. Suddenly, the\u00a0demand for immunization increased 10\u00a0fold. The World Health Organization\u00a0(WHO) now believes that the degree of\u00a0alarm regarding the lethality of H1N1 was\u00a0exaggerated, but at the time, the WHO\u00a0launched a joint e\u0094ort to provide vaccines.\u00a0\u201cThe WHO had to prepare a vaccine\u00a0and give it to producers, including\u00a0the institute. There would not be vaccines\u00a0for everyone, but the agreement between\u00a0the Butantan Institute and Sanofi\u00a0guaranteed the priority of acquiring vaccines\u00a0manufactured overseas and allowed\u00a0the immunization of some 80 million\u00a0people, \u201csays Isaias Raw.<\/p>\n

Even before the application of new\u00a0technologies, Butantan may be able to\u00a0export influenza vaccines to countries\u00a0in the Northern Hemisphere. Today, the\u00a0productivity of the plant is seasonal.\u00a0Manufacturing begins around September,\u00a0when the WHO defines the three\u00a0types of flu virus that are most prevalent\u00a0in that period and sends samples to the\u00a0manufacturers. For Butantan, the level\u00a0of production is high until April, when\u00a0actual vaccination begins, and then the\u00a0plant suspends all activity until the following\u00a0September. \u201cIn this period, we\u00a0could produce the combination of vaccines\u00a0of the Northern Hemisphere and\u00a0supply them to people who live above\u00a0the equator in Brazil as well as in countries\u00a0like Venezuela, Colombia and Guyana,\u201d\u00a0says Isaias Raw. \u201cToday, immunization\u00a0arrives too late in these regions\u00a0and is not really e\u0094ective.\u201d<\/p>\n

Viruses and embryos<\/strong>
\nIt took 7 years to complete the factory\u00a0because it was necessary to overcome\u00a0a series of obstacles. In addition to bureaucratic\u00a0issues related to choosing a
\nconstruction company for the project\u00a0and importing special equipment, such\u00a0as centrifuges, it was also necessary to\u00a0develop a machine that destroys what\u00a0is left of the eggs after the liquid full of\u00a0viruses has been isolated. This leftover\u00a0material has to be reduced to a powder\u00a0to be safely transported and incinerated.\u00a0This material must be destroyed\u00a0to prevent it from becoming food for\u00a0birds and other animals \u2013 a few live viruses\u00a0would be su\u0002cient to accidentally\u00a0spread the disease. \u201c\u201cIt is a very complex\u00a0process, which involves a specific\u00a0technique for injecting the virus into\u00a0each egg, separating the liquid in which\u00a0the virus reproduces, and then purifying\u00a0and re-purifying it to allow the environmentally\u00a0friendly treatment of the\u00a0waste material,\u201d says Hernan Chaimovich,\u00a0superintendent of the Butantan\u00a0Foundation. The vaccine immunizes\u00a0against three types of influenza, but\u00a0the production process is concentrated\u00a0on one strain at a time. Before moving\u00a0to the next strain, the plant must stop\u00a0all activity for a few days and undergo\u00a0a rigorous disinfection process. Sanofi\u00a0monitored the production of the first\u00a0batches and testified that the plant had\u00a0been validated within the rules of the\u00a0European Union. Investments for the\u00a0implementation of the project exceeded\u00a0R$100 million, with funding from\u00a0the state government of S\u00e3o Paulo, the\u00a0Ministry of Health and the Butantan\u00a0Foundation. \u201cThese figures become irrelevant\u00a0relative to the millions of dollars\u00a0in savings that Brazil will realize\u00a0when it does not need to buy products\u00a0from international laboratories,\u201d said\u00a0Jorge Kalil, director general of the Butantan\u00a0Institute, in an article \u00a0ublished\u00a0by Folha de S\u00e3o Paulo newspaper. \u201cThis\u00a0tremendous advancement in science\u00a0and technology turned Brazil into the\u00a0only country in Latin America that currently\u00a0produces influenza vaccines.\u201d<\/p>\n

Global Alliance<\/strong>
\nThe vaccine production capacity of public\u00a0institutions in Brazil caught the attention\u00a0of the Bill and Melinda Gates\u00a0Foundation, which has also made contact\u00a0with institutions in other countries.\u00a0Last year, Butantan was visited by Tachi\u00a0Yamada, president of the Global Health\u00a0Program of the Gates Foundation, who\u00a0was interested in learning more about\u00a0the production capacity of the institution\u00a0in S\u00e3o Paulo. The Gates Foundation,\u00a0a charitable organization started\u00a0by the founder of Microsoft, is seeking\u00a0partners to produce vaccines at a low\u00a0cost so that these vaccines can be provided\u00a0to developing countries. A proposal\u00a0for collaboration with Butantan,\u00a0the Serum Institute of India, and Bio-Manguinhos in Rio de Janeiro was recently
\nformalized. The partnership aims\u00a0to produce approximately 30 million\u00a0doses of a pentavalent vaccine against\u00a0diphtheria, tetanus, pertussis, hepatitis
\nB and Haemophilus influenzae B (which\u00a0causes meningitis and other diseases).\u00a0Butantan delivered a proposal to provide\u00a0100 million doses at $1.50 each, which is\u00a0scheduled for delivery in 2014, and this\u00a0proposal is currently awaiting approval.\u00a0The partnership of the Bill and Melinda\u00a0Gates Foundation with the Global Alliance\u00a0for Vaccines and Immunization\u00a0(GAVI) has already produced remarkable\u00a0effects in its search for new suppliers.\u00a0Last month, four pharmaceutical\u00a0giants, GSK, Merck, Johnson & Johnson\u00a0and Sanofi-Aventis, agreed to sell GAVI\u00a0vaccines against diarrhea and rotavirus\u00a0at cost. This represents a 70% reduction\u00a0in the retail price of the vaccine.\u00a0Furthermore, two companies in India,\u00a0the Serum Institute and Panacea Biotec,\u00a0committed to providing the pentavalent\u00a0vaccine at just $1.75 per dose.<\/p>\n","protected":false},"excerpt":{"rendered":"Butantan develops technology to increase production and lower costs","protected":false},"author":11,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[169],"tags":[],"coauthors":[98],"class_list":["post-67934","post","type-post","status-publish","format-standard","hentry","category-technology"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/67934","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/11"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=67934"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/67934\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=67934"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=67934"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=67934"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=67934"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}